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DNA Adduct Formation of 4-Aminobiphenyl and Heterocyclic Aromatic Amines in Human Hepatocytes Gwendoline Nauwelaers,† Erin E. Bessette,‡ Dan Gu,‡ Yijin Tang,‡ Julie Rageul,† Valerie Fessard,§ Jian-Min Yuan,|| Mimi C. Yu,|| Sophie Langou€et,*,†,^ and Robert J. Turesky*,‡,^ †
)
Institut de Recherche en Sante Environnement Travail, EA4427 SeRAIC, Universite Rennes 1, IFR 140, 2 Avenue du Pr L Bernard, 35043 Rennes, France ‡ Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health, Albany, New York 12201, United States § Anses Laboratoire de Fougeres, La Haute MarcheJavene, BP 90203, 35302 Fougeres cedex, France Masonic Comprehensive Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States
bS Supporting Information ABSTRACT:
DNA adduct formation of the aromatic amine, 4-aminobiphenyl (4-ABP), a known human carcinogen present in tobacco smoke, and the heterocyclic aromatic amines (HAAs), 2-amino-9H-pyrido[2,3-b]indole (ARC), 2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine (PhIP), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), and 2-amino-3,8-dimethylmidazo[4,5-f]quinoxaline (MeIQx), potential human carcinogens, which are also present in tobacco smoke or formed during the high-temperature cooking of meats, was investigated in freshly cultured human hepatocytes. The carcinogens (10 μM) were incubated with hepatocytes derived from eight different donors for time periods up to 24 h. The DNA adducts were quantified by liquid chromatographyelectrospray ionization mass spectrometry with a linear quadrupole ion trap mass spectrometer. The principal DNA adducts formed for all of the carcinogens were N-(deoxyguanosin-8-yl) (dG-C8) adducts. The levels of adducts ranged from 3.4 to 140 adducts per 107 DNA bases. The highest level of adduct formation occurred with ARC, followed by 4-ABP, then by PhIP, MeIQx, and IQ. Human hepatocytes formed dG-C8-HAA-adducts at levels that were up to 100-fold greater than the amounts of adducts produced in rat hepatocytes. In contrast to HAA adducts, the levels of dG-C8-4-ABP adduct formation were similar in human and rat hepatocytes. These DNA binding data demonstrate that the rat, an animal model that is used for carcinogenesis bioassays, significantly underestimates the potential hepatic genotoxicity of HAAs in humans. The high level of DNA adducts formed by ARC, a carcinogen produced in tobacco smoke at levels that are up to 100-fold higher than the amounts of 4-ABP, is noteworthy. The possible causal role of ARC in tobacco-associated cancers warrants investigation.
’ INTRODUCTION 4-Aminobiphenyl (4-ABP) is a prototypical aromatic amine and a recognized human urinary bladder carcinogen.13 4-ABP served as an antioxidant in the rubber industry prior to the discovery of its carcinogenic activity.2,3 In the United States and r 2011 American Chemical Society
many developed countries, strict federal regulations have drastically diminished the industrial usage of 4-ABP and other carcinogenic Received: February 27, 2011 Published: April 01, 2011 913
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Chemical Research in Toxicology aromatic amines, but 4-ABP can still be found as a contaminant in color additives,4,5 paints,6 food colors,7 leather, and textile dyes.8,9 4-ABP and other aromatic amines also arise in diesel-exhaust particles1012 and cooking oil fumes.13 A major source of exposure to 4-ABP occurs through tobacco smoke: 4-ABP is present in mainstream tobacco smoke at levels ranging from 0.1 to 4.3 ng/ cigarette.14,15 Another potential source of exposure to 4-ABP occurs through the usage of commercial hair dyes.16,17 Heterocyclic aromatic amines (HAAs) are carcinogens in experimental laboratory animals and are potential human carcinogens.18 HAAs are structurally related to aromatic amines: both classes of compounds undergo common pathways of bioactivation.19,20 The principal source of exposure to HAAs occurs through the consumption of well-done cooked meats: the concentrations of HAAs can range from 75% of the 10 μM dose); however, both carcinogens are poorly metabolized in rat hepatocytes, and a majority of the dose remains unmetabolized, even after 24 h.37,38 There are also interspecies differences in regioselectivity of the P450 1A2 oxidation of PhIP and MeIQx. Rat P4501A2 catalyzes oxidation at the heterocyclic rings of PhIP and MeIQx to produce detoxication products; N-oxidation products of both HAAs account for less than 2% of the dose in rat hepatocytes.37,38 In contrast to the rat P450 1A2 orthologue, the catalysis of ring oxidation products of PhIP and MeIQx, by human P450 1A2, is negligible,72,73 and a principal metabolic pathway for both HAAs in human hepatocytes occurs by P450 1A2-mediated N-oxidation (Figure 4).37,38 In the case of 4-ABP, up to 23% of the dose (10 μM) was converted into N-oxidation products in rat hepatocytes.74 The DNA binding data show that both human and rat P450 1A2 orthologues efficiently carry out the N-oxidation of 4-ABP and that comparable levels of DNA adducts are formed in hepatocytes of both species (Figures 6 and 7). The major pathways of metabolism of MeIQx and PhIP have been extensively characterized in rat and human hepatocytes,37,38,75,76 and in vivo of both species,40,77 but knowledge about the metabolism of ARC is limited. The metabolism of ARC was examined in the human liver tumor HepG2 cell line;78 however, these cells do not express P450 1A279 and are devoid of UGTs,78 and thus, the ARC metabolites formed may not accurately reflect the biotransformation pathways that occur for ARC in humans. Recombinant human P450 1A2 enzyme does catalyze N-oxidation of the exocyclic amine group of ARC, as well as ring oxidation at the C3 and C6 atoms of the ARC heteronucleus.80,81 Both human and rodent uridine diphosphateglucuronosyltransferases are involved in the detoxication of MeIQx and PhIP.40,75,77,82 There is also evidence for the formation of Nglucuronide conjugates of ARC in rodents.83 Glutathione S-transfereases catalyze the detoxication of N-oxidized PhIP metabolites,84,85 but this family of enzymes has not been found to be involved in the detoxication of N-oxidized metabolites of MeIQx84 or ARC.86 We have detected a number of metabolites of ARC in human hepatocytes, by LC-ESI/MS/MS (Supporting Information, Figure S-3 A and Figure S-3 B): ARC undergoes extensive oxidation, and acetyl, sulfate, or glucuronide conjugates are formed. We plan to elucidate the pathways of ARC metabolism and the principal pathways involved in ARC-DNA adduct formation in hepatocytes, to establish human biomarkers of this HAA. 921
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ARC undergoes N-oxidation by human P450 1A2, as well as P450s 1A1 and 2C9/2C10, which are highly expressed in the colon and respiratory tract.80 Moreover, human NAT1 and NAT2, and SULT1A1, which are expressed in liver and extrahepatic tissues, catalyze the binding of HONH-ARC to DNA.86,87 Thus, the potential for ARC to undergo metabolism and induce DNA damage in multiple organs that are in direct or indirect contact with tobacco smoke is great. Given the large amounts of ARC that arise in tobacco smoke25,26 and the elevated levels of ARC found in the urine of smokers in comparison to nonsmokers,88 studies investigating the potential role of ARC in the carcinogenicity of liver and gastrointestinal cancers associated with tobacco smoking89 are warranted.
HON-PhIP-N2-Gl, N2-(β-1-glucosiduronyl-2-(hydroxyamino)1-methyl-6-phenylimidazo[4,5-b]pyridine; HON-PhIP-N3-Gl, N3-(β-1-glucosiduronyl-2-(hydroxyamino)-1-methyl-6-phenylimidazo[4,5-b]pyridine; PhIP-N2-Gl, N2-(β-1-glucosiduronyl-2amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; PhIP-N3-Gl, N3-(β-1-glucosiduronyl-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; dG-C8-4-ABP, N-(deoxyguanosin-8-yl)-4-ABP; dG-N2-N4-ABP, N-(deoxyguanosin-N2-yl)-4-aminobiphenyl; dG-C8-IQ, N-(deoxyguanosin-8-yl)-IQ; dG-N2-IQ, 5-(deoxyguanosinN2-yl)-IQ; dG-C8-ARC, N-(deoxyguanosin-8-yl)-ARC dG-C8MeIQx, N-(deoxyguanosin-8-yl)-MeIQx; dG-N 2 -MeIQx, 5-(deoxyguanosin-N2-yl)-MeIQx; dG-C8-PhIP, N-(deoxyguanosin8-yl)-PhIP.
’ ASSOCIATED CONTENT
’ REFERENCES
bS
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Additional information as noted in text. This material is available free of charge via the Internet at http://pubs.acs.org. Supporting Information.
’ AUTHOR INFORMATION Corresponding Author
*(S.L.) Tel. 02 23 23 48 06. Fax: 02 23 23 47 94. E-mail: sophie.
[email protected]. (R.J.T.) Tel. 518-474-4151. Fax 518473-2095. E-mail:
[email protected]. Author Contributions ^
These authors contributed equally to this work.
Funding Sources
This work was funded by R01 CA122320 (to E.E.B., D.G, and R.J.T.) and R01 CA134700 (to E.E.B, Y.T., and R.J.T.) from the National Cancer Institute, and also partially supported by R01 CA80205 (to M.C.Y.), R01 CA98497 (to J.-M.Y.), and R01 CA144034 (to J.-M.Y.) from the National Cancer Institute. We also thank Inserm, la Ligue contre le cancer, the region Bretagne and Anses (to G.N. and S.L.) for financial aid and College Doctoral International of the Universite Europeenne de Bretagne for travel fellowship (to G.N.).
’ ABBREVIATIONS CHO, Chinese hamster ovary cells; EROD, ethoxyresorufin Odeethylation; HAA, heterocyclic aromatic amine; LC-ESI/MS/MS, liquid chromatography/electrospray ionizationtandem mass spectrometry; LC-ESI/MS/MSn, liquid chromatographyelectrospray ionization/multistage tandem mass spectrometry; LIT MS, linear quadrupole ion trap mass spectrometer; MROD, methoxyresorufin O-deethylation; NAT, N-acetyltransferase; SULT, sulfotransferase; 4ABP, 4-aminobiphenyl; IQ, 2-amino-3-methylimidazo[4,5-f]quinoline; ARC, 2-amino-9H-pyrido[2,3-b]indole; HONH-ARC, 2-hydroxyamino-9H-pyrido[2,3-b]indole; MeIQx, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline; HONH-MeIQx, 2-hydroxyamino-3, dimethylimidazo[4,5-f]quinoxaline; IQx-8-COOH, 2-amino-3methylimidazo[4,5-f]quinoxaline-8-carboxylic acid; 8-CH2OH-IQx, 2-amino-8-(hydroxymethyl)-3-methylimidazo[4,5-f]quinoxaline; MeIQx-N2-Gl, N 2-(β-1-glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline; HON-MeIQx-N2-Gl, N2-(β-1-glucosiduronyl)-2-(hydroxyamino)-3,8-dimethylimidazo[4,5-f]quinoxaline; MeIQxN2-SO3H, N2-(3,8-dimethylimidazo[4,5-f]quinoxalin2-yl-sulfamic acid;2-amino-3-methylimidazo[4,5-f]quinoline (IQ); PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; HONH-PhIP, 922
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